Multiple myeloma (MM) is still incuable B-cell malignancy affecting more than 14,000 Americans annually. Myeloma tumor cells can survive even the most aggressive treatment available today, leading to disease relapses. The long-term goal of this project is to develop more effective cytostatic therapies to eradicate myeloma cells. We recently made a novel and exciting discovery that anti-beta2-microglobulin (beta2M) monoclonal antibodies (mAbs) had strong apoptotic activity in both established myeloma cell lines and primary myeloma cells from patients. The mAbs selectively target and kill myeloma cells in coculture with normal hematopoietic cells without damaging normal blood cells, including CD34+ stem cells in vitro, and were active and therapeutic in vivo in xenograft mouse models of myeloma. Anti-beta2M mAb-induced apoptosis in myeloma cells were not blocked by high concentrations of soluble beta2M, IL-6, or other myeloma growth and survival factors, and was stronger than apoptosis observed with chemotherapy drugs currently used to treat MM (e.g., dexamethasone). The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Moreover, we also showed that the mAbs may prevent or slowdown bone destruction in patients. Thus, we hypothesize that anti-beta2M mAbs may be used as therapeutic agents to treat patients with MM. This hypothesis will be tested by the following aims. Aim 1 will examine the mechanisms of anti-beta2M mAb-induced apoptosis in myeloma cells. Using normal plasma or B cells as controls, we will define the role of surface MHC class I and class I-like molecules in these responses, and examine surface proteins binding to, the downstream kinases, and intracellular signaling and apoptosis pathways induced by anti-beta2M mAbs. Aim 2 will elucidate the mechanism of anti-beta2M mAb-mediated protection of myeloma bone disease, and Aim 3 will develop strategies to enhance the efficacy of anti-beta2M mAbs to induce apoptosis in myeloma cells. These novel studies may lead to the development of anti-beta2M mAbs as the first clinically useful and effective therapeutic mAbs for the treatment of MM and potentially other malignancies that express surface beta2M and MHC class I molecules.